Chronic psychological stress is known to trigger anxiety and lead to cognitive impairment. In general, acute stress is considered good and essential for adaptation while chronic stress is believed to be bad and responsible for maladaptive changes causing anxiety and cognitive disturbances. The question of what triggers bad effects of stress is quite intriguing. Publications from our last R15 suggest oxidative stres as a biochemical trigger causing behavioral and cognitive deficits in rats. Recently, we have demonstrated that social defeat induced psychological stress in rats lead to anxiety-like behavior and memory impairment, associated with heightened oxidative stress, reduced antioxidant defense and increased inflammation within the hippocampus. Interestingly, elevated oxidative stress and inflammation impair mitochondrial function, weakening normal stress response. Moreover, hippocampal neurons are considered highly susceptible to mitochondrial impairment. In preliminary studies, using a hippocampal cell line we observed that chronic oxidative stress decreased mitochondrial respiration, membrane potential, and ATP production. Antioxidant tempol treatment reversed these effects, suggesting involvement of oxidative stress in regulation of mitochondrial function, considered critical for normal behavior and cognition. Thus, role of oxidative stress initiated mitochondrial impairment in psychological stress-induced behavioral and cognitive deficits must be revealed. We propose that chronic psychological stress increases oxidative stress, compromising mitochondrial function and integrity, leading to activation of proteolytic and apoptotic pathways. This contributes to degradation of antioxidant enzymes, reducing antioxidant defense, impairing detoxification and resulting in behavioral and cognitive deficits. Aim 1 will identify role of oxidative stress in anxiety-like behavior and cogniive impairment upon social defeat (SD) stress in rats. Effect of antioxidant tempol treatment prior to or following SD, will also be examined. Tempol by reducing oxidative stress should ameliorate SD-induced deficits. Aim 2 seeks to determine role of oxidative stress in regulation of synaptic plasticity upon social defeat in rats using in vivo electrophysiological recordings in the sub-regions Cornu Ammonis 1 and dentate gyrus of the hippocampus. Changes in synaptic plasticity will be assessed utilizing long-term potentiation measurement. We expect tempol to ameliorate SD-induced decrease in synaptic plasticity in rats. Aim 3 will identify the mechanism of SD-mediated impairments in rats. Hippocampus, amygdala and pre-frontal cortex will be isolated for analysis of mitochondrial function, inflammation, caspase and calpain activation. We expect SD rats to show decreased respiration, low membrane potential, and reduced ATP production. Inflammation, calpain and caspase expression are expected to increase with a concomitant decrease in the antioxidant pool. Antioxidant tempol treatment is expected to attenuate these effects. This renewal of our R15 application will provide the groundwork for future pharmacological strategies to limit detrimental effects of chronic stress.